Chronic Lung Allograft Rejection: Mechanisms and Therapy

Abstract

Lung transplantation is a therapeutic option for patients with end-stage pulmonary disorders. Unfortunately, due to post-lung transplant complications, both infectious and noninfectious, it is only a treatment and not a cure. Importantly, despite induction combined with triple or quadruple maintenance immunosuppressive therapy, chronic lung rejection, in the form of obliterative bronchiolitis or its clinical correlate bronchiolitis obliterans syndrome (BOS), continues to be highly prevalent and is the major limitation to long-term survival. In this review we evaluate the presentation, diagnosis, histopathology, pathologic mechanisms, risk factors, and prevention/treatment options for BOS. A better understanding of the risk factors and how it relates to the pathologic mechanisms of chronic lung allograft rejection should lead to better pharmacologic targets to prevent/treat this syndrome without increasing the recipient's risk for infections.

Increased myeloid cell hypoxia-inducible factor-1 delays obliterative airway disease in the mouse

“…As a result, the complete loss of the tracheal epithelium was delayed in mVHL -/-mice. The importance of epithelial injury in OAD development is well established, 3,26 and reduced injury may explain the delay in OAD development in our study. However, epithelial regeneration does not explain the reason for initially reduced inflammatory response.…”

“…Bronchial epithelial damage and injury of the subepithelial structures seem to be the key initiating event in the development of OB. 3,4 Ischemiareperfusion injury is one of the most important causes of early allograft injury and may lead to primary graft dysfunction that in turn contributes to the development of OB. 5,6 Therefore, interventions targeting early immune activation could well result in reduced long-term complications.…”

Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis

“…Keywords: interstitial lung disease; lung allograft rejection; lung transplantation; pleuroparenchymal fibroelastosis; pulmonary fibrosis Increasing evidence suggests that chronic lung allograft dysfunction following lung transplantation is a heterogeneous condition that includes bronchiolitis obliterans syndrome as well as other types of allograft dysfunction. Although bronchiolitis obliterans syndrome, characterized clinically by irreversible obstructive deficits in pulmonary function tests, [1][2][3][4] remains the major cause of late mortality, we recently described a distinct form of chronic lung allograft dysfunction demonstrating restrictive pulmonary function decline, which we designated restrictive allograft syndrome, 5 and which accounts for 25-35% of chronic lung allograft dysfunction. 5,6 Radiologically, a significant proportion of these patients demonstrated an unusual pattern of interstitial fibrosis, often upper lobe-predominant, associated with traction bronchiectasis in computed tomography scans.…”

Obliterative Airway Remodeling

“…Recent years have witnessed a breakthrough in management of acute cellular rejection and chronic allograft dysfunction, and its main morphologic hallmark, bronchiolitis obliterans, has emerged as a major complication and the leading cause of death. 3 The outcome in patients with OAR who did not undergo lung transplantation varies significantly and depends first and foremost on the underlying setting or disease and, thereby, on the responsiveness to medication (eg, steroid therapy). The involvement of a large number of effector molecules and their corresponding receptors in OAR has been demonstrated recently; however, the general inaccessibility of the local remodeling process by sampling at bronchoscopy has hampered adequate molecular profiling of the lesions.…”

“…This type is most commonly observed after hematopoietic stem cell transplantation or allogeneic lung transplantation, in which it significantly limits long-term survival and is considered the hallmark of chronic graft dysfunction. 3 The second variant is bronchiolitis obliterans with intraluminal polyps, in which mesenchymal protrusions bulge into the lumen of the airways and the adjacent alveoli. This type is referred to as "organizing pneumonia" (formerly "bronchiolitis obliterans organizing pneumonia"), and represents a nonspecific pattern.…”